FIELD OF THE INVENTION

The invention relates to the use of 4-(lH-Indol-4-yl)-6-(morpholin-4-yl)-12- [(lS,4S)-2-oxa-5-azablcydo[2 2.1]heptan-5-ylmethyl]-8-oxa-3,5,10- tnazatncydo[7 4.0.02,7jjtrideca-l(13),2(7),3,5,9,l l-hexaene or a pharmaceutically acceptable salt thereof to treat or prevent B cell lymphoma. This compound has the chemical structure:

BACKGROUND OF THE INVENTION

The phosphoinositide 3-kinases (PI3Ks) constitute a family of lipid kinases involved in the regulation of a network of signal transduction pathways that control a range of cellular processes PI3Ks are classified into three distinct subfamilies, named class I, II, and III based upon their substrate specificities. Class IA PI3Ks possess a pllOo, rΐ ΐqb, or rΐ ΐqd catalytic subunit complexed with one of three regulatory subunits, p85o, r85b or r55d Class IA PI3Ks are activated by receptor tyrosine kinases, antigen receptors, G-protein coupled receptors (GPCRs), and cytokine receptors. The class IA PI3Ks primarily generate phosphatidylinositol-3, 4,5- triphosphate (PI(3,4,5)P ₃ ), a second messenger that activates the downstream target AKT. The consequences of biological activation of AKT include tumour cell progression, proliferation, survival and growth, and there is significant evidence suggesting that the PI3K/AKT pathway is dysregulated in many human cancers. Additionally, PI3K activity has been implicated in endocrinology, cardiovascular disease, immune disorders and inflammation It has been established that PI3K- rΐ ΐqd plays a critical role in the recruitment and activation of immune and inflammatory cells. PI3K-pl 10d is also upregulated in a number of human tumours and plays a key role in tumour cell proliferation and survival. Compounds which are able to modulate rΐΐqd activity have Important therapeutic applications in cancer.

Despite therapeutic advances, the currently available treatments for several haematological cancers, in particular B cell lymphoma, remain unsatisfactory. Although a high proportion of patients show response to initial lines of therapy, many fail to achieve disease remission, and some experience disease relapse. As a consequence, there is considerable need for the design and development of novel medicines for the alleviation of these disorders, in particular agents that regulate molecular targets associated with haematological cancer development and progression.

The compound of the present invention has been characterised and described in international patent application published as WO2015/121657.

SUMMA Y OF THE INVENTION

References to the compound (4-(lH-Indol-4~yl)~6~(morpholin~4-yi)--12--[(lS,4S)~ 2~oxa-5-azabicydo[2 2.1]heptan~5-ylmethyl]~8-oxa-3,5,10- triazafricydo[7.4.0.02,7]trideca-l(13),2(7),3,5,9,l l-hexaene) or may include references to the pharmaceutically acceptable salt.

Where a chemical structure is shown, the accuracy of the structure takes preference over the compound name.

The present invention is based on a compound or a pharmaceutically acceptable salt thereof for use in the treatment of B cell lymphoma wherein the compound has the structure:

B cell lymphoma may be one or more of diffuse large B-ce!l lymphoma, follicular non-Hodgkin lymphoma, chronic lymphocytic leukaemia, small lymphocytic lymphoma, mantle cell lymphoma, marginal zone lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy ceil leukaemia, primary central nervous system lymphoma, primary intraocular lymphoma or Waldenstrom macroglobulinemia. In one embodiment, the compound is for use in the treatment of diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukaemia, small lymphocytic lymphoma or Waldenstrom macroglobulinemia.

As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, metbanesuifonic, ethanesulfonic, ethanedisulfonic, salicylic, stearic, benzenesulfonic or p-toluenesulfonic acid. The compound is preferabiy provided as its succinate salt.

The compound for use is preferably administered once or twice daily.

Preferabiy, the 4-(lH-Indol-4-yl)-6-(morpholin-4-yl)-12-[(lS,4S)-2-oxa-5- azabicyclo[2.2 l]beptan-5~ylmethyl]-8~oxa-3,5,lQ- triazatricyclo[7.4.0.02,7]trideca-l(13),2(7),3,5,9,l l-hexaene or a pharmaceutically acceptable salt is administered orally, preferabiy with wafer, and is preferably administered after the patient has consumed food. In a favourable embodiment, the 4-(lH-Indol-4~yl)~6-(morphoiin~4-yl)-12-[(lS,4S)-2-oxa~5- azabicyclo[2.2.1]heptan-5-ylmethyl]~8-oxa-3,5,10- triazatricyclo[7.4.0.02,7]trideca-l(13),2(7),3,5,9,l l-hexaene or a pharmaceutically acceptable salt is administered with approximately 240 mL of water and within one hour after the patient has consumed food. For this purpose, 4-(lH-Indol-4-yl)-6-(morpholin-4-yl)-12-[(lS,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10- triazatricyclo[7.4.0.02,7]trideca-l(13),2(7),3,5,9,l l-hexaene or a pharmaceutically acceptable salt may be administered in capsule form. For ora! administration, the compound can be administered as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules. Preferred pharmaceutical compositions of the invention are tablets and capsules.

A compound of the invention may also be formulated with an agent which reduces degradation of the substance by processes other than the norma! metabolism of the patient, such as anti-bacterial agents, or inhibitors of protease enzymes which might be the present in the patient or in commensurai or parasite organisms living on or within the patient, and which are capable of degrading the compound.

Liquid dispersions for ora! administration may be syrups, emulsions and suspensions.

Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylceliulose, carboxymethylceliulose, or polyvinyl alcohol.

The compound for use is preferably administered in a dose of at least 50 mg daily, more preferably 100 mg daily, and still more preferably 150 mg daily, and most preferably 200 mg daily.

The compound for use may be administered in a dose of up to 600 mg daily, more preferably up to 500 mg daily, still more preferably up to 400 mg daily, still more preferably up to 300 mg daily, and most preferably up to 200 mg daily.

The compound for use may be administered in a dose of between 50 and 400 mg daily, preferably between 200 and 400 mg daily, more preferably 200 mg daily.

The compound for use may be administered in capsule form.

The compound for use is advantageously administered to a patient having already received conventional first-line treatment, e.g. treatment with a regimen comprising one or more of conventional cytotoxic agents such as cyclophosphamide, doxorubicin, vincristine, prednisone or chlorambucil, a CD20 antibody with or without a drug conjugate such as rituximab, obinutuzumab or ibritumomab, a BCL2 inhibitor such as venetoclax, a BTK inhibitor such as ibrutinib, an immunomodulatory imide drug such as !ena!idomide, a proteasome inhibitor such as bortezomib, radiation therapy, agents that modulate anti-tumour immunity including agents modulating immune checkpoints (e,g, PD(L)1 targeting agents such as pembro!izumab or nivoiumab, CTLA-4 targeting agents such as ipilimumab, agents targeting 0X40, LAG3, TIM3 or other immunomodulatory molecules), bi-specific T-cell engaging therapies, or cellular therapies (e.g. adoptive T-ceil therapy, CAR-T therapy). The compound for use may advantageously be administered to patients who have already received a BTK inhibitor such as ibrutinib ibrutinib and/or a BCL2 inhibitor such as venetoclax therapy.

In one embodiment, treatment comprises administering an effective amount of 4-

(lH-Indol~4-yl)-6-(morpboiin-4~yi)-12-[(lS,4S)-2~oxa-5- azabicyclo[2.2.1]heptan-5~ylmethyl]-8~oxa-3,5,lQ- triazatricyclo[7.4.0.02,7]trideca-l(13),2(7),3,5,9,l l-hexaene or a pharmaceutically acceptable salt thereof, in a 28 to 35 day cycle, wherein 4~(1H~ Indoi-4-yi)-6-(morpbolin-4-yi)-12-[(lS,4S)-2-oxa-5-azabicyci o[2.2.1]hepfan-5~ ylmetbyl]~8~oxa-3,5,lQ~tnazatricyclo[7.4.0.Q2,7]frideca-l(13 ),2(7),3,5,9,ll~ hexaene is administered daily or twice a day to the patient for 3 or 4 weeks, and 1 week no 4-(lH-Indo!-4~yl)~6-(morphoiin~4-yl)-12-[(lS,4S)~2-oxa-5~ azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10- triazatricyclo[7.4.0.02,7]trideca-l(13),2(7),3,5,9,l l-hexaene is administered.

The invention also provides a pharmaceutical composition for use in the treatment of B cell lymphoma comprising an embodiment of 4-(lH-Indol-4-yl)-6-(morpholin- 4-yl)-12-[(lS,4S)-2-oxa-5-azabicycio[2.2,l]heptan-5-ylmethyl ]-8-oxa-3,5,10~ triazatricyclo[7.4.0.02,7]trideca-l(13),2(7),3,5,9,l l-hexaene as previously defined and a pharmaceutically acceptable excipient.

Preferably, the compound is at least 60% enantiomericaily pure, more preferably 70%, still more preferably 80%, still more preferably 90%, still more preferably 95%, still more preferably 99%.

The pharmaceutically excipient may comprise one or more of lactose monohydrate, microcrystalline cellulose, crospovidone, hydroxypropyi cellulose, magnesium stearate and sodium iauryi sulfate. In one embodiment, the pharmaceutical formulation consists of lactose monohydrate, microcrystalline cellulose, crospov!done, hydroxypropyi cellulose, magnesium stearate and sodium lauryl sulfate and 4-(1H·-^oI-4-gI)-d-(hΊqf|·ioϋh-4·-gI)-12-[(15,45)-2·-o cq-5- azabicydo[2,2.1]beptan-5-ylmethyl]-8-Qxa-3,5,10~

triazatricydo[7,4.0.02,7]trideca-l(13),2(7),3,5,9,l l-hexaene as its succinate salt.

In one embodiment the pharmaceutical composition is for use in the treatment of one or more of diffuse large B-ceil lymphoma, follicular non-Hodgkin lymphoma, chronic lymphocytic leukaemia, small lymphocytic lymphoma, mantle cell lymphoma, marginal zone lymphoma, Burkitt lymphoma, iymphoplasmacytlc lymphoma, hairy cell leukaemia, primary central nervous system lymphoma, primary intraocular lymphoma or Waldenstrom macroglobulinemia. Advantageously, the pharmaceutical composition is for use in the treatment of B~ cell lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukaemia, small lymphocytic lymphoma or Waldenstrom macroglobulinemia.

The pharmaceutical composition may comprise at least one second agent selected from the group consisting of conventional cytotoxic agents such as cyclophosphamide, doxorubicin, vincristine, prednisone or chlorambucil, a CD20 antibody with or without a drug conjugate such as rituximab, obinutuzumab or ibritumomab, a BCL2 inhibitor such as venetodax, a BTK inhibitor such as ibrutinib, a MEK inhibitor such as trametinib, an immunomodulatory imide drug such as lenalidomlde, a proteasome inhibitor such as bortezomib, radiation therapy, agents that modulate anti-tumour immunity including agents modulating immune checkpoints (e.g. PD(L)1 targeting agents such as pembrolizumab or nivoiumab, CTLA-4 targeting agents such as ipilimumab, agents targeting 0X40, LAGS, TIM3 or other immunomodulatory molecules), bi-specific T-ceil engaging therapies, or cellular therapies (e.g. adoptive T-cell therapy, CAR-T therapy) as a combined preparation for simultaneous, sequential or separate use in therapy. Preferably, the second agent is selected from a p70S6K inhibitor, a BTK and TEC family inhibitor and a MEK1 inhibitor.

The invention also provides a kit comprising at least 4-(lH-Indol-4-yl)-6- (morpholin-4-yl)-12-[(lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan -5-ylnnethyl]-8- oxa-3,5,10-triazatricyclo[7.4.0.Q2,7]trideca-l(13),2(7),3,5, 9,ll-hexaene or a pharmaceutically acceptable salt thereof, preferably the succinate salt, and at least one agent selected from the group consisting of conventional cytotoxic agents such as cyclophosphamide, doxorubicin, vincristine, prednisone or chlorambucil, a CD20 antibody with or without a drug conjugate such as rituximab, obinutuzumab or ibritumomab, a BCL2 inhibitor such as venetoclax, a BTK inhibitor such as ibrutinib, a MEK inhibitor such as trametinib, an immunomodulatory imide drug such as !enalidomide, a proteasome inhibitor such as bortezomib, radiation therapy, agents that modulate anti-tumour immunity Including agents modulating Immune checkpoints (e.g. PD(L)1 targeting agents such as pembroiizumab or nivolumab, CTLA-4 targeting agents such as ipilimumab, agents targeting 0X40, LAGS, T1 3 or other immunomodulatory molecules), bi-specific T-ce!! engaging therapies, or cellular therapies (e.g. adoptive T-cell therapy, CAR-T therapy) as a combined preparation for simultaneous, sequential or separate use in therapy.

The invention also provides a method of treating or preventing B cell lymphoma in a patient comprising administering to the patient a therapeutically effective amount of at least one compound as previously defined, the pharmaceutical composition as previously defined or using the kit as previously defined.

The method may be for treating or preventing diffuse large B-celi lymphoma, follicular non-Hodgkin lymphoma, chronic lymphocytic leukaemia, small lymphocytic lymphoma, mantle cell lymphoma, marginal zone lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukaemia, primary central nervous system lymphoma, primary intraocular lymphoma or Waldenstrom macroglobulinemia. Advantageously, the method is for treating or preventing B- ceil lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukaemia, small lymphocytic lymphoma or Waldenstrom macroglobulinemia.

The method may provide that the compound is administered in a dose of at least 50 mg daily, more preferably 100 mg daily, and still more preferably 150 mg daily, and most preferably 200 mg daily.

The method may provide that the compound is administered in a dose of up to 600 mg daily, more preferably up to 500 mg daily, still more preferably up to 400 mg daily, still more preferably up to 300 mg daily, and most preferably up to 200 mg daily. The method may provide that the compound is administered in a dose of between 50 and 400 mg daily, preferably between 200 and 400 mg daily, more preferably 200 mg daily.

The compound for use may be administered once daily, twice daily, three times daily or four times daily. Preferably, the compound is administered once or twice daily, and more preferably, the compound is administered once daily.

The method may provide that the compound is administered to a patient who has already received conventional first-line treatment, e.g. treatment with a regimen comprising one or more of conventional cytotoxic agents such as cyclophosphamide, doxorubicin, vincristine, prednisone or chlorambucil, a CD20 antibody with or without a drug conjugate such as rituximab, obinutuzumab or ibritumomab, a BCL2 inhibitor such as venetodax, a BTK inhibitor such as ibrutinib, an immunomodulatory imide drug such as ienaiidomide, a proteasome inhibitor such as bortezomib, radiation therapy, agents that modulate anti-tumour immunity including agents modulating immune checkpoints (e.g. PD(L)1 targeting agents such as pembrolizumab or nivoiumab, CTLA-4 targeting agents such as ipilimumab, agents targeting 0X40, LAGS, TIMS or other immunomodulatory molecules), bi-specific T-cell engaging therapies, or cellular therapies (e.g. adoptive T-ceil therapy, CAR-T therapy). The compound for use may advantageously be administered to patients who have already received a BTK inhibitor such as ibrutinib ibrutinib and/or a BCL2 inhibitor such as venetodax therapy.

The invention also provides a method of treating B ceil lymphoma is a patient in need thereof, comprising : administering an effective amount of 4-(lH-Indoi-4-yl)- 6-(morpholin-4-yi)-12-[(lS,4S)-2-oxa-5-azabicyclo[2.2.1]hept an-5-yimethyi]-8- oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-l(13),2(7),3,5, 9,ll-hexaene or a pharmaceutically acceptable salt thereof, e.g. the succinate salt.

The invention also provides a method for treating advanced or metastatic B cell lymphoma in a patient in need thereof, comprising : administering an effective amount of 4-(lH-Indol-4-yl)-6-(morpholin-4-yl)-12-[(lS,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-y!methy!]-8-oxa-3,5,10- triazatricydo[7,4.0.02,7]trideca-l(13),2(7),3,5,9,l l-bexaene or a pharmaceutically acceptable salt thereof, wherein the patient has progression of the B ceil lymphoma after previous administration of another therapy.

The method may provide that the previous administration of another therapy is a therapy for advanced or metastatic B cell lymphoma.

Optionally in the method the previous administration of another therapy is an administration of another chemotherapeutic agent, e.g, treatment with a regimen comprising one or more of conventional cytotoxic agents such as cyclophosphamide, doxorubicin, vincristine, prednisone or chlorambucil, a CD20 antibody with or without a drug conjugate such as rituximab, obinutuzumab or ibritumomab, a BCL2 inhibitor such as venetoclax, a BTK inhibitor such as ibrutinib, an immunomodulatory imide drug such as !ena!idomide, a proteasome inhibitor such as bortezomib, radiation therapy, agents that modulate anti-tumour immunity including agents modulating immune checkpoints (e.g. PD(L)1 targeting agents such as pembrolizumab or nivolumab, CTLA-4 targeting agents such as ipilimumab, agents targeting 0X40, LAGS, TIMS or other immunomodulatory molecules), bi-specific T-ceN engaging therapies, or cellular therapies (e.g. adoptive T-ceii therapy, CAR-T therapy), The compound for use may advantageously be administered to patients who have already received a BTK inhibitor such as ibrutinib ibrutinib and/or a BCL2 inhibitor such as venetoclax therapy.

In the method, administering an effective amount of 4-(lH-Indol-4-yl)-6- (morpholin-4-yl)-12-[(lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan -5-ylmethyl]-8- oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-l(13),2(7),3,5, 9,ll-hexaene or a pharmaceutically acceptable salt thereof may comprise orally administering a total daily dose of about 200 mg to about 400 mg, preferably 200 mg, of the 4-(lH- Indoi-4-yl)-6-(morpholin-4-yi)-12-[(lS,4S)-2-oxa-5-azabicyci o[2,2, l]heptan~5- ylmethyl]-8-oxa-3,5,10-triazatricydo[7.4.0.02,7]trideca-l(13 ),2(7),3,5,9,ll- hexaene.

In the method, administering an effective amount of 4-(lH-Indol-4-yl)-6- (morpholin-4-yl)-12-[(lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan -5-ylmethyl]-8- oxa-3,5,lQ~triazatricycio[7.4.Q.G2,7]trideca-l(13),2(7),3,5, 9,ll-hexaene or a pharmaceutically acceptable salt thereof may comprise oraliy administering, once or twice daily, about 200 g to about 400 mg, preferably 200 g, of the 4-(lH- IndQl-4-yi)-6-(morpbo!in-4-yl)-12-[(lS,4S)-2-oxa-5-azabicydo [2.2, l]heptan-5- y!metby!]-S-oxa-3,5,10-triazatricydo[7.4,0,02,7]trideca-l(13 ),2(7),3,5,9,ll- hexaene.

Preferably, the patient has a histological or cytological diagnosis of B cell lymphoma.

Administering an effective amount of 4-(lH-Indol-4-y!)-6-(morpholin-4-yl)-12- [(lS,4S)-2-oxa-5-azabicyclo[2,2.1]heptan-5-yimethyi]-8-oxa-3 ,5,lG- triazatricydo[7,4.0.02,7]trideca-l(13),2(7),3,5,9,l l-hexaene or a pharmaceutically acceptable salt thereof may comprise administration in a 28 to 35 day cycle, wherein 4-(lH-Indol~4-yl)-6-(morpholin-4-yl)-12-[(lS,4S)-2-oxa- 5~azabicyclo[2.2.1]beptan-5-ylmetbyi]-8-oxa~3,5,10- triazatricydo[7,4.0.02,7]trideca-l(13),2(7),3,5,9,l l-hexaene is administered daily or twice a to the patient for 3 or 4 weeks, and 1 week no 4~(lH~Indol-4-yi)-

6-(morpholin-4-yl)-12-[(lS,4S)-2-oxa-5-azabicyclo[2.2.1]h eptan-5-ylmethyl]-8- oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-l(13),2(7),3,5, 9,ll-hexaene is administered,

The method may further comprise administering to the patient a therapeutically effective amount of at least one second agent selected from the group consisting of conventional cytotoxic agents such as cyclophosphamide, doxorubicin, vincristine, prednisone or chlorambucil, a CD20 antibody with or without a drug conjugate such as rituximab, obinutuzumab or ibritumomab, a BCL2 inhibitor such as venetodax, a BTK inhibitor such as ibrutinib, a MEK inhibitor such as trametinib, an immunomodulatory imide drug such as lenalidomide, a proteasome inhibitor such as bortezomib, radiation therapy, agents that modulate anti-tumour immunity including agents modulating immune checkpoints (e.g. PD(L)1 targeting agents such as pembro!izumab or nivolumab, CTLA-4 targeting agents such as ipiiimumab, agents targeting 0X40, LAGS, TIM3 or other immunomodulatory molecules), bi-specific T-cell engaging therapies, or cellular therapies (e.g. adoptive T-cell therapy, CAR-T therapy). Administration of the compound and the at least one second agent may be separate, sequential or simultaneous.

The invention also provides a compound or a pharmaceutically acceptable salt thereof for use in the treatment of B cell lymphoma, wherein the compound has the formula :

and wherein the compound is administered as a total daily dose of 200 mg and wherein the compound is administered to a patient having already received treatment with one or more of cyclophosphamide, doxorubicin, vincristine, prednisone and/or rituximab therapy

DESCRIPTION OF THE INVENTION At the clinical cut-off date, 21 patients with relapsed or refractory B cell lymphoma had received treatment in this study; 6 patients were enrolled and treated with 50 mg daily, 3 patients with 100 mg daily, 7 patients with 200 mg daily and 5 patients with 400 mg daily. The first patient enrolled started treatment with 50 mg 4-(lH-Indol-4-yl)-6- (morpholin-4-yl)-12-[(lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan -5-ylmethyl]-8- oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-l(13),2(7),3,5, 9,ll-hexaene.

Progress of each patient in each cohort up to the clinical cut-off date is summarized in Table 1 and Table 2

A summary of efficacy outcomes in the study to date is in Table 3. Complete response was noted in subjects 01004, 01013, 01018 and 01020 while partial response has been reported for subjects 01010, 01011 and 01017 and stable disease in subjects 01006, 01007, 01009 and 01019. Among subjects starting treatment at doses of >200 mg daily with response data reported, the ORR is 50% (6/12). Patients achieving at least a partial response included those with indolent NHL, MCL and DLBCL. Thus there is evidence that this agent is effective as monotherapy in lymphoma that has recurred following prior treatment.

Table 3 Treatment Response by Cohort An independent review of the imaging from the study was performed by ABX-CRO, This independent review was largely concordant with the assessment of the study site (MD Anderson Cancer Center; MDACC). In the independent review, a single subject was classified differently (subject 01018, classified as complete response by MDACC and partial response by ABX-CRO; Table 4).

Table 4 Independent Review of Treatment Response

Synthesis of the compound of the present invention

Reagents and conditions: 1) K2CG3, ethyl glycolate, DMF, 115°C; 2) (i) chlorosulfonyl isocyanate, CH2Q2, 0-10°C then rt (ii) water, 75°C (Hi) NaOH max temp 40°C; 3) POC , N,N~dimethylaniiine, 107°C; 4) morpholine, MeGH, rt; 5) N,N,-dimethylacrylamide, PdCl2(PPh ₃ )2, NaOAc, DMF, 110°C; 6) NaI0 ₄ , QsQ ₄ , THF, water, rt; 7) indole-4-boronic acid pinacol ester, PdChCPPiTah, sodium carbonate, dioxane, water, 102°C.

/. Ethyl-3-amino-5-bromofuro[2,3-b]pyridine-2-carboxylate

To a 10L flask under SNhCg) was added 5-bromo-2-ch!oropyridine-3-carbonitriie (435g, 2.0mol, leq), DMF (2790mL) and potassium carbonate (553g, 4.0mol, 2eq). This was followed by the addition of ethyl glycolate (208, 2mL, 2.2mol, l. leq). The reaction mixture was heated to 115°C overnight, Upon completion, the reaction mixture was cooled to rt and water (13.1L) was added, this led to the formation of a precipitate. The mixture was stirred for 20mins, then filtered. The resulting brown solid was dried at 50°C, slurried in EtiCkheptane (9: 1, 2.8L) and filtered to give 405.6g. Further purification via soxhlet extraction using TBME (4.5L) yielded the product as a yellow solid (186g, 34%), This procedure was repeated twice,

8.53 (d, J=2,0Hz, 1H), 8.07 (d, J=2.0Hz, 1H), 5.00 (br. s., 2H), 4,44 (q, J=7.QHz, 2H), 1.44 (t, J=7.0Hz, 3H).

MS (ES ⁺ ) 309 (100%, [M + Na] ⁺ ), 307 (100%, [M + Na] ⁺ ).

//, 12 -Bromo -8 -oxa -3, 5,10 -triazatricydo[7.4.0.0 ² ' ⁷ ]trideca -1(9), 2(7), 10,12- tetraene -4, 6 -dione

To ethyl-3-amino-5-bromofuro[2,3-b]pyridine-2-carboxylate (239. Og, Q.84moi, leg) dissolved in CH2CI2 (5.5L) was added chlorosulfonyl isocyanate (87.6mL, l.Omol, 1.2eq) dropwise at 0-10°C. The resulting reaction was stirred for 30min, stripped to dryness and the resulting solid ground to a fine powder, Water (5.5L) was added to the solid and the suspension was heated at 75°C for Ih, After cooling to rt, solid NaQH (335g, 8.4moi, lOeq) was added allowing the reaction to exotherm (maximum temperature 40°C). The reaction was cooled to 0-10°C and the pH adjusted to 5-6 using 5M HCi (~1L). The reaction was stirred for 30mins, then filtered. The solid was washed with water (2.3L) and pulled dry. Further drying in a vacuum oven at 40°C yielded the product as a brown solid (193g, 76%). This procedure was repeated twice.

¹ H NMR (400MHz, DMSO -de) d _H : 12.01 (br. s., IH), 11,58 (br. s, IH), 8.72 (d, J-2,0Hz, IH), 8.59 (d, J=2.0Hz, IH).

MS (ES-) 282 (100%, [M + H] ⁺ ).

Hi. 12 -Bromo -4, 6 -dichioro -8 -oxa -3, 5, 1 Q -triazatricyc!of? .4.0.0 ^2,7 ]tndeca-

1(9), 2(7), 3, 5, 10, 12 -hexaene

To 12-bromo-8-oxa-3,5,10-triazatricyclo[7.4.0.0 ² ' ⁷ ]trideca-l(9),2(7),10,12- tetraene-4,6-dione (387g, 1.27mol, leg) was added POCI3 (6070mL) and N,N- dimethy!aniiine (348mL, 2,8moi, 2.2eq). The mixture was heated at 1Q7°C for lOh, Once cooled to rt, solvent was removed in vacuo azeotroping with toluene (3 x 3.9L). The resulting residue was partitioned between CH2CI2 (12.76L) and water (3.91) and the phases separated. The organic phase was washed with water (2 x 3.91). The combined aqueous was back-extracted with CH2CI2 (7,71) and the combined organics dried over MgSG4, filtered and stripped to yield the product as brown solid (429g, ~quant.),

8.78 (d, J= 2,5Hz, IH), 8.72 (d, J= 2.5Hz, IH). iv. 12 -bromo -4 - chloro -6 -( morpholin -4 -yl ) -8-oxa -3,5, 10 - triazatricyc!o[7.4.0.0 ² ' ⁷ ]thdeca -1 ( 9) ,2(7) ,3, 5.10, 12 -hexaena

To 12-bromo-4,6-dich!oro-8-oxa -3,5,10-triazatricyclo[7.4,Q,0 ² ' ⁷ ]trideca·· l(9),2(7),3,5,10,12-hexaene (419.3g, 1.32mo! _f leq) in MeOH (8588mL) was added Morpholine (259mL, 2.90mol, 2.2eq) at rt. After stirring for 2h, water (0.8L) was added. It was then cooled to G-5°C and stirred for an additional 30mins. The resulting solid was filtered, washed with water (5.2L) and pulled dry. Further purification by silica gel column chromatography with Ch Ch/EtGAc (1 ; 0-9: 1) yielded the desired product (419g, 84%).

1H), 4.07-

dimethylprop-2 -enamide

To 12-bromo-4-chlcro-6-(morpholin-4-yl)-8-oxa-3,5,10- triazatricycio[7,4.0.0 ^¾7 ]trideca-l(9),2(7),3,5,lQ,12-hexaene (60g, 0.15mol, leq) was added /V,A/-dimethyiacrylamide (16.7mL, 0.15moi, leq), PdChCPPhah (3.4g, 4.5mmol, 0.03eq) and NaOAc (4Gg, 0.45mol, 3eq) in DMF (1.2L). The reaction was heated at 110°C for 7h. This process was repeated 3 times and batches combined. Once cooled down to rt, solvent was removed In vacuo and the resulting residue was partitioned between CH2CI2 (6.5L) and water (5.5L). The phases were separated and the aqueous phase was extracted with CH2CI2 (2 x 4L). The combined organics were washed with brine (2 x 4L), dried over MgSC¾, filtered and stripped. The resulting solid was slurried in EtOAc/heptane (1 : 1, 0.8L) for SOmins, filtered, washed and washed with EtOAc/heptane (1 : 1, 2 x 450mL), Further drying in a vacuum oven at 40°C yielded the desired product as an orange solid (203. Og, 86%).

8.70 (s, 2H), 7.82 (d, J=15.6Hz, 1H), 7,07 (d, J=15.6Hz, 1H), 4.11-4.19 (m, 4H), 3.85-3.93 (m, 4H), 3,22 (s, 3H), 3.11 (s, 3H). MS (ES ⁺ ) 388 (100%, [M + H] ⁺ ).

vi . 4 - Chloro -6 -( morpholin -4 -yl) -8 -oxa -3,5, 10-thazathcydo[7.4.0 0 ² ' ⁷ ]thdeca - 1(9), 2(7), 3, 5, 10, 12 -hexaene-12 -carhaidehyde (2E)-3-[4-chloro-6-(morpholin-4-yl)-8-oxa-3,5,10-triazatricy clo[7.4.0.0 ⁷ ]trideca- l(9),2(7),3,5,10,12-hexaen-12-yl]-N,N-dimethylprop-2-enamide (124. Og,

0.39mol, leq) was dissolved in THF (12.4L) at 65°C. Once cooled to 35°C, water (4.1L), NaIG ₄ (205.4g, 1.17mol, 3eq) and 0s0 ₄ (2.5wt% in ¾uGH, 80.3mL, 2%) were added. The reaction was stirred at rt for 6Gh, The reaction was cooled to 0- 5°C _; stirred for BOmins then filtered. The solid was washed with water (545mL) and pulled dry. The crude product was combined with two further batches (2 x 118.3g scale) and slurried in water (6.3L) for BOmins at rt. The solids were filtered, washed with water (1.6L) and pulled dry. Further drying in a vacuum oven yielded the desired product as a pink solid (260g, 88%)

¹ H NMR (400MHz, CDCI ₃ : MeOD, 9: 1) d _H : 10.13 (s, 1H), 9.04 (d, J= 2.0Hz, 1H), 8.91 (d, J=2.0Hz, 1H), 3.99-4.13 (m, 4H), 3.73-3.84 (m, 4H).

MS (ES ⁺ ) 351 (100%, [M+MeOH + H] ⁺ ).

vii . 4-(lH~Indol-4~y!)-6 -( morpholin -4 -yl ) -8 -oxa -3, 5,10- triazatricydof 7.4.0 0 ² · ⁷ ]trideca -1 (9), 2,4, 6,10,12 - hexaene-12 - carhaldehyde

To 4-cbio!O-6-(morpho!in-4-y!)-8-oxa-3,5,lQ-tnazatricyc!o[7,4.G .0' ^{? 7} ]trideca- l(9),2(7),3,5,10,12-hexaene-12-carbaldehyde (164.4g, 0,52mol, leq) was added indole-4-boronic acid pinacol ester (376. Og, 1.55mol, Beq), PdCl2(PPh3)2 (72. Og, O. lOmoi, 2eq) and sodium carbonate (110.2g, 1.04moi, 2eq) in dioxane (16.4L) / water (5.8L). Reaction mixture was refluxed for Ih. It was then cooled to 60~70°C. Water (9.81), brine (4.9L) and EtOAc (9.5L) were added. The phases were separated and the aqueous phase extracted with EtOAc (3 x 9.51) at 60-65°C. The combined organics were dried over MgS0 ₄ , filtered and stripped. The resulting solid was slurried in CH2CI2 (4.75L) for 30mins, filtered, washed with CH2Q2 (3 x 238mL) and pulled dry. Further drying in a vacuum oven at 40°C yielded Intermediate X as a yellow solid (135.7g, 66%).

¹ H NMR (300MHz, CDCI ₃ ) d _H : 11.27 (br. s, IH), 10.26 (s, IH), 9.16 (d, J= 2.3Hz, IH), 9.11 (d, J=2.3Hz, IH), 8.18 (d, J= 7.5Hz, IH), 7.58-7.67 (m, 2H), 7.49 (t, J=2.8Hz, IH), 7.23 (t, J= 7,7Hz, IH), 4.08-4.16 (m, 4H), 3.83-3.90 (m, 4H).

MS (ES ⁺ ) 432.0 (100%, [M + MeOH + H] ).

4 -(lH-Indol-4 -yl ) -6 {morpholin 4 -yl ) -12 {( 1 S,4S ) -2 -oxa -5-azabicydo[2.2.1 Jheptan- 5-ylmethyl]-8-oxa-3,5,l 0-triazatricydo[7.4.0.0 ^2,7 ]trideca-l (13), 2(7), 3, 5, 9,11 - hexaene (A)

X A To a suspension of intermediate X (7.Q0g, 17,53mmoi, leq), (lS,4S)-2~oxa-5- azabicydo[2.2.1]heptane hydrochloride (7, 13g, 52.58mmol, 3eq) and NaOAc (4.31g, 52,58mmol, 3eq) in anhydrous C^Ch (ISOmL) was added NaBH(OAc)3 (7,43g _f 35.06mmol, 2eq), The reaction mixture was stirred at rt overnight. Then, it was partitioned with IN NaOH (lOOmL) and extracted with CH2CI2 (3 x 2Q0mL). The combined organic extracts were washed with brine (50mL) then dried over gSC¾ and the solvent was removed in vacuo. Purification by silica gel column chromatography with EtOAc/MeOH (1 :0-7; 1) yielded the product A (the compound of the present invention) as a white solid (6.02g, 71%).

8.65 (d, .7=2.1 Hz, 1H), 8.58 (d, 7=2,1 Hz, 1H), 8.37 (br. s., 1H), 8.24 (dd, J= 7.5, 0.9 Hz, 1H), 7.62 (td, J= 2.6, 0.8 Hz, 1H), 7.53 (d, 7=8, 1 Hz, 1H), 7.37-7.41 (m, 1H), 7.31-7.37 (m, 1H), 4.47 (s, 1H), 4.22-4.30 (m, 4H), 4.18 (d, 7=8.1 Hz, 1H), 3.98 (d, 7=2.3 Hz, 2H), 3.91-3.97 (m, 4H), 3.70 (dd, 7=7.9, 1.7 Hz, 1H), 3.53 (s, 1H), 2.94 (dd, 7= 10.0, 1.5 Hz, 1H), 2.64 (d, 7= 10.2 Hz, 1H), 1.97 (dd, 7=9.8, 1.9 Hz, 1H), 1.80 (dt, 7=9.8, 1.1 Hz, 1H). MS (ES ⁺ ) 483, 1 (100%, [M + H] ⁺ ).

4 -( lH-Indoi-4-yi)-6 -(morphoiin -4-yi)-12-[(l 5,45 ) -2 -oxa -5-azabicydo[2.2.1 Jheptan- 5-ylmethyl]-8-oxa-3,5,l 0-t azatricydo[7.4.0.0 ^{2 7} ]trideca-l (13), 2(7), 3, 5, 9,11 - hexaene; succinic acid (AS)

Compound A (100.0 gram, 207.2 mmol) was dissolved in a mixture of DCM (1.0 L, 10 vols) and EtOH (500 mL, 5 vols). The solution was filtered through a cleaned P4 frit and the frit was washed with MC/EtOH 2: 1 (300 mL, 0.3 vols). In another vessel, succinic acid (26.92 gram, 228.0 mmol, 1.10 eq) was dissolved in ethanol (1.0 L, 10 vols). The solution was filtered through a P4 frit and the frit washed with ethanol (200 mL, 2 vols). The compound A solution was charged to a cleaned reactor and concentrated at atmospheric pressure to 13 vols (Tend = 41°C).

1. EtOH (5 vols) was added and distilled atmospherically (Tend = 49°C). Precipitation started during concentration.

2. EtOH (5 vols) was added and distilled atmospherically (Tend = 73°C).

3. Additional solvent was removed (Tend = 75°C).

4. Milli-Q water (1Q0 mL, 1 vol) was added and distillation continued until T = 76°C.

The filtered solution of succinic acid was dosed to the compound A suspension in ethanol at reflux, followed by milli-Q water (50 mL, 0.5 vols), later additional mii!i- Q water was added (1 vol). The suspension was heated at reflux for 5 hours while slowly distilling of solvent. The suspension was then allowed to cool to rT and stirred for ± 10 hours. The product was filtered off and washed with EtOH (4 times 1 vols). The filter cake was dried on the filter and for 21 hours at 50°C in the vacuum oven to give product AS (the succinate salt of the compound of the present invention) as a white to pale yellow solid. Yield : 119.05 gram = 198.2 mmol = 95.7%.

^X H NMR (400MHz, DMF ~d7) d _H : 1132 (br. s, 1H), 8.67 (s, 2H), 8.29 (d, 7=7.4 Hz, 1H), 7.70 (m, 1H), 7.64 (d, 7= 7.4 Hz, 1H), 7.58 (m, 1H), 7.28 (t, 7=7,4 Hz, 1H), 4.39 (m, 1H), 4.22 (m, 4H), 4.04 (m, 3H), 3.94 (m, 4H), 3.61 (m, 2H), 2.87 (m,

1H), 2.57 (m, 5H), 1.69 (m, 1H), 1.51 (m, 1H).

MS (ES ⁺ ) 483.2 (100%, [M t-H] ),